Gene-Gene Associations with the Susceptibility of Kawasaki Disease and Coronary Artery Lesions

PLoS One. 2015 Nov 30;10(11):e0143056. doi: 10.1371/journal.pone.0143056. eCollection 2015.

Abstract

Kawasaki disease (KD) is a systemic vasculitis primarily affecting children < 5 years old. Genes significantly associated with KD mostly involve cardiovascular, immune, and inflammatory responses. Recent studies have observed stronger associations for KD risk with multiple genes compared to individual genes. Therefore, we investigated whether gene combinations influenced KD susceptibility or coronary artery lesion (CAL) formation. We examined 384 single-nucleotide polymorphisms (SNPs) for 159 immune-related candidate genes in DNA samples from KD patients with CAL (n = 73), KD patients without CAL (n = 153), and cohort controls (n = 575). Individual SNPs were first assessed by univariate analysis (UVA) and multivariate analysis (MVA). We used multifactor dimensionality reduction (MDR) to examine individual SNPs in one-, two-, and three-locus best fit models. UVA identified 53 individual SNPs that were significantly associated with KD risk or CAL formation (p < 0.10), while 35 individual SNPs were significantly associated using MVA (p ≤ 0.05). Significant associations in MDR analysis were only observed for the two-locus models after permutation testing (p ≤ 0.05). In logistic regression, combined possession of PDE2A (rs341058) and CYFIP2 (rs767007) significantly increased KD susceptibility (OR = 3.54; p = 4.14 x 10(-7)), while combinations of LOC100133214 (rs2517892) and IL2RA (rs3118470) significantly increased the risk of CAL in KD patients (OR = 5.35; p = 7.46 x 10(-5)). Our results suggest varying gene-gene associations respectively predispose individuals to KD risk or its complications of CAL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Child, Preschool
  • Coronary Artery Disease / epidemiology
  • Coronary Artery Disease / genetics*
  • Cyclic Nucleotide Phosphodiesterases, Type 2 / genetics
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Interleukin-2 Receptor alpha Subunit / genetics
  • Male
  • Mucocutaneous Lymph Node Syndrome / epidemiology
  • Mucocutaneous Lymph Node Syndrome / genetics*
  • Polymorphism, Single Nucleotide*

Substances

  • Adaptor Proteins, Signal Transducing
  • CYFIP2 protein, human
  • IL2RA protein, human
  • Interleukin-2 Receptor alpha Subunit
  • Cyclic Nucleotide Phosphodiesterases, Type 2
  • PDE2A protein, human

Grants and funding

The work was supported by Ministry of Science and Technology, Taiwan (MOST 102-2314-B-182-053-MY3, MOST103-2410-H-264-004 and 104-2314-B-758-002-MY3) and Chang Gung Memorial Hospital (CMRPG8C1082, CMRPG8B0212,CMRPG8D1561 and CMRPG8D0521). This work was carried out as a cooperative project of the institutes of all authors. None of the institutes had an influence on the collection, analysis, and interpretation of data or on the preparation of the manuscript.